A levosalbutamol hydrochloride atomized inhalation solution composition and preparation method thereof

Abstract

The present invention provides a levosalbutamol hydrochloride nebulized inhalation solution composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The composition comprises levosalbutamol hydrochloride, a costabilizer, an osmotic pressure regulator, a pH regulator, and a solvent. Edetate disodium, gentisic acid, and sodium diacetate are used as costabilizers. The costabilizers enhance the stability of the composition and extend its storage time. Furthermore, the composition simplifies the preparation process without nitrogen filling protection, reduces the requirements for production equipment, is simple and easy to operate, and has low production costs.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a levosalbutamol hydrochloride atomized inhalation solution composition and a preparation method thereof. Background Art

[0002] Asthma is currently the most common respiratory disease in the world, with a high prevalence. Currently, the main medications for asthma control include β2-receptor agonists, glucocorticoids, and systemic hormones. β2-receptor agonists are the most widely used anti-asthma medication in clinical practice, accounting for approximately 60% of the anti-asthma drug market. Racemic salbutamol currently plays a pivotal role in the treatment of bronchial asthma both domestically and internationally. In vitro studies have shown that the levorotatory form of salbutamol has a 100-fold stronger affinity for β-receptors than the dextrorotatory form, and the physiological effects of the racemic form are largely provided by the levorotatory form. Furthermore, dextrorotatory salbutamol can cause adverse reactions such as headaches, dizziness, palpitations, and finger tremors. Clinical studies have shown that compared to its racemic form, levorotatory salbutamol hydrochloride offers the advantages of higher efficacy, milder side effects, and better tolerability.

[0003] In March 1999, the U.S. Food and Drug Administration (FDA) approved the use of levosalbutamol hydrochloride as an alternative to racemic salbutamol for the treatment of asthma. Therefore, replacing the existing racemic form with a single optically active form is an inevitable trend in clinical medication. According to the United States Pharmacopoeia, the concentration of 5-hydroxysalbutamol in a nebulized levosalbutamol inhalation solution should be ≤ 0.10%, and the impurity D should be ≤ 0.08%.

[0004] The structural formula of impurity D is as follows:

[0005]

[0006] (R)-5-[2-(tert-Butylamino)-1-hydroxyethyl]-2-hydroxybenzaldehyde

[0007] U.S. Patent No. 6,451,289B contains a formula of levosalbutamol hydrochloride, sodium chloride, and water for injection. This patent discloses a method for preparing a nebulized inhalation solution for levosalbutamol hydrochloride. During the preparation process, nitrogen is used to displace oxygen from the solution until the dissolved oxygen level is less than 1 ppm. The headspace of the product after filling is then filled with nitrogen for protection. The product is then packaged in an oxygen-impermeable aluminum-plastic film to ensure that the residual oxygen content in the container is below 2%. However, nitrogen filling during production, through the dispensing tank, the headspace of the low-density polyethylene ampoule, and the aluminum-plastic film, is challenging and can easily lead to breakage and leakage during transportation.

[0008] Chinese patent CN110898039A discloses a levosalbutamol hydrochloride solution preparation for inhalation and a preparation method thereof, comprising: levosalbutamol hydrochloride and / or its hydrate; an osmotic pressure regulator; a pH regulator; a stabilizer; and a solvent. The patent discloses a levosalbutamol hydrochloride solution preparation for inhalation. The patent utilizes sodium bisulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, or acetylcysteine ​​as a stabilizer, eliminating the need for nitrogen protection during packaging. However, the levosalbutamol hydrochloride solution preparation exhibits a total impurity content of approximately 0.256% after storage at 40°C for 30 days. Furthermore, there is no mention of whether the growth of impurity D can be suppressed, indicating that the stability of the levosalbutamol hydrochloride solution preparation in the patent remains to be improved. Summary of the Invention

[0009] The present invention aims to solve the problems existing in the prior art and provides a levosalbutamol hydrochloride atomized inhalation solution composition and a preparation method thereof. The composition has a simple preparation method, high stability and a long storage time.

[0010] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0011] The present invention provides a levosalbutamol hydrochloride atomized inhalation solution composition, comprising levosalbutamol hydrochloride, a costabilizer, an osmotic pressure regulator, a pH regulator and a solvent; wherein,

[0012] The co-stabilizers are edetate disodium, gentisic acid and sodium diacetate.

[0013] Furthermore, the salbutamol hydrochloride nebulized inhalation solution composition comprises 0.033 mg / mL-0.500 mg / mL salbutamol hydrochloride, 0.050 mg / mL-0.500 mg / mL co-stabilizer and 5.00 mg / mL-15.00 mg / mL osmotic pressure regulator, and is adjusted to a pH value of 3.30-4.50 by a pH regulator, with the remainder being solvent.

[0014] Preferably, the salbutamol hydrochloride nebulized inhalation solution composition comprises 0.103 mg / mL-0.417 mg / mL salbutamol hydrochloride, 0.067 mg / mL-0.133 mg / mL co-stabilizer, 8.00 mg / mL-10.000 mg / mL osmotic pressure regulator, and is adjusted to a pH value of 3.70-4.30 by a pH regulator, and the remainder is solvent.

[0015] More preferably, the levosalbutamol hydrochloride nebulized inhalation solution composition comprises 0.360 mg / mL levosalbutamol hydrochloride, 0.100 mg / mL co-stabilizer, 9.000 mg / mL osmotic pressure regulator, and is adjusted to a pH value of 4.11 by a pH regulator, with the remainder being solvent.

[0016] Preferably, in the co-stabilizer, the weight ratio of edetate disodium, gentisic acid, and sodium diacetate is 1:0.5-1.2:0.3-0.7. Further, the weight ratio of edetate disodium, gentisic acid, and sodium diacetate is 1:0.7-0.9:0.4-0.6. More preferably, the weight ratio of edetate disodium, gentisic acid, and sodium diacetate is 1:0.77:0.44.

[0017] Preferably, the osmotic pressure regulator is an inorganic salt; the inorganic salt is at least one of sodium chloride, magnesium chloride or calcium chloride.

[0018] Preferably, the pH adjuster is an acid; the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.

[0019] Preferably, the solvent is water for injection.

[0020] The single dose of the levosalbutamol hydrochloride aerosol inhalation solution composition of the present invention is 3 mL.

[0021] Another object of the present invention is to provide a method for preparing the above-mentioned salbutamol hydrochloride aerosol inhalation solution composition, comprising the following steps:

[0022] S1. adding an osmotic pressure regulator and a co-stabilizer to a solvent and dissolving them to obtain a solution A;

[0023] S2. adjusting the pH of solution A to a target value with a pH adjuster to obtain solution B;

[0024] S3. Levosalbutamol hydrochloride is added to solution B, and then solvent is added to the volume to obtain solution C;

[0025] S4. Filter solution C to obtain the product.

[0026] Furthermore, in step S1, the temperature of the solvent is ≤30°C; preferably, the temperature of the solvent is 10-25°C.

[0027] Furthermore, in step S2, the target pH value is 3.3-4.5; preferably, the target pH value is 3.7-4.3.

[0028] Furthermore, in step S4, the filtering refers to filtering with a microporous membrane having a pore size of ≤3 μm; preferably, the filtering refers to filtering twice with a microporous membrane having a pore size of 0.22 μm.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The stability of the levosalbutamol hydrochloride nebulized inhalation solution composition is improved by the action of a co-stabilizer. After storage at 40° C. for 6 months, no 5-hydroxysalbutamol and impurity D were detected, and the total impurity content was less than or equal to 0.08%. Therefore, the levosalbutamol hydrochloride nebulized inhalation solution composition of the present invention can significantly improve stability, thereby increasing storage time;

[0031] (2) The salbutamol hydrochloride nebulized inhalation solution composition is sealed without nitrogen protection, which simplifies the preparation process, reduces the requirements for production equipment, is simple and easy to operate, has low production cost, and is easy to industrialize. DETAILED DESCRIPTION

[0032] The following non-limiting examples are provided to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way. The following is merely an illustrative description of the scope of the present invention, and those skilled in the art may make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0033] The present invention is further described below by way of specific examples. Unless otherwise specified, the various chemical reagents used in the examples of the present invention were obtained through conventional commercial channels.

[0034] Example 1

[0035] Levosalbutamol hydrochloride atomized inhalation solution composition

[0036] Prescription: 0.033 mg / mL salbutamol hydrochloride, 0.050 mg / mL co-stabilizer and 5.00 mg / mL sodium chloride, and adjusted to pH 3.30 with hydrochloric acid, the remainder is water for injection.

[0037] The co-stabilizers are edetate disodium, gentisic acid and sodium diacetate in a mass ratio of 1:1.2:0.7.

[0038] Preparation method:

[0039] S1. Based on the prescribed amount, the osmotic pressure regulator and the co-stabilizer are added to 50% of the solvent per unit dose volume to obtain Solution A; wherein the single dose volume in this embodiment is 3 mL; the prescribed amount is based on the single dose volume, and the corresponding amounts of salbutamol hydrochloride, co-stabilizer, and osmotic pressure regulator are calculated according to the corresponding concentrations;

[0040] S2. The pH of solution A was adjusted to 3.30 using hydrochloric acid to obtain solution B;

[0041] S3. Add salbutamol hydrochloride to solution B based on the prescribed amount, and then add water for injection to the unit dose volume to obtain solution C;

[0042] S4. Filter solution C twice using a 0.22 μm filter membrane, transfer the solution into an ampoule, and then seal the ampoule directly without nitrogen filling.

[0043] Example 2

[0044] Levosalbutamol hydrochloride atomized inhalation solution composition

[0045] Prescription: 0.500 mg / mL salbutamol hydrochloride, 0.500 mg / mL co-stabilizer, 15.00 mg / mL sodium chloride, and sulfuric acid to a pH of 4.50, the remainder is water for injection.

[0046] The co-stabilizers are edetate disodium, gentisic acid and sodium diacetate in a mass ratio of 1:0.5:0.3.

[0047] Preparation method:

[0048] S1. Based on the prescribed amount, the osmotic pressure regulator and the co-stabilizer are added to 90% of the solvent per unit dose volume to obtain Solution A; wherein the single dose volume in this embodiment is 3 mL; the prescribed amount is based on the single dose volume and the corresponding amounts of salbutamol hydrochloride, co-stabilizer, and osmotic pressure regulator are calculated based on the corresponding concentrations;

[0049] S2. The pH of solution A was adjusted to 4.50 using sulfuric acid to obtain solution B;

[0050] S3. Add salbutamol hydrochloride to solution B based on the prescribed amount, and then add water for injection to the unit dose volume to obtain solution C;

[0051] S4. Filter solution C twice using a 0.22 μm filter membrane, transfer the solution into an ampoule, and then seal the ampoule directly without nitrogen filling.

[0052] Example 3

[0053] Levosalbutamol hydrochloride atomized inhalation solution composition

[0054] Prescription: 0.103 mg / mL salbutamol hydrochloride, 0.067 mg / mL co-stabilizer, 8.000 mg / mL calcium chloride, and phosphoric acid to a pH of 3.75, the remainder is water for injection.

[0055] The co-stabilizers are edetate disodium, gentisic acid and sodium diacetate in a mass ratio of 1:0.7:0.4.

[0056] Preparation method:

[0057] S1. Based on the prescribed amount, the osmotic pressure regulator and the co-stabilizer are added to 80% of the solvent per unit dose volume to obtain Solution A; wherein the single dose volume in this embodiment is 3 mL; the prescribed amount is based on the single dose volume, and the corresponding amounts of salbutamol hydrochloride, co-stabilizer, and osmotic pressure regulator are calculated based on the corresponding concentrations;

[0058] S2. The pH of solution A was adjusted to 3.75 using phosphoric acid to obtain solution B;

[0059] S3. Add salbutamol hydrochloride to solution B based on the prescribed amount, and then add water for injection to the unit dose volume to obtain solution C;

[0060] S4. Filter solution C twice using a 0.22 μm filter membrane, transfer the solution into an ampoule, and then seal the ampoule directly without nitrogen filling.

[0061] Example 4

[0062] Levosalbutamol hydrochloride atomized inhalation solution composition

[0063] Prescription: 0.500 mg / mL salbutamol hydrochloride, 0.500 mg / mL co-stabilizer, 15.00 mg / mL sodium chloride, and adjusted to pH 4.32 with citric acid, the remainder is water for injection.

[0064] The co-stabilizers are edetate disodium, gentisic acid and sodium diacetate in a mass ratio of 1:0.9:0.6.

[0065] Preparation method:

[0066] S1. Based on the prescribed amount, the osmotic pressure regulator and the co-stabilizer are added to 79% of the solvent per unit dose volume to obtain Solution A; wherein the single dose volume in this embodiment is 3 mL; the prescribed amount is based on the single dose volume, and the corresponding amounts of salbutamol hydrochloride, co-stabilizer, and osmotic pressure regulator are calculated based on the corresponding concentrations;

[0067] S2. Using citric acid to adjust the pH of solution A to 4.32 to obtain solution B;

[0068] S3. Add salbutamol hydrochloride to solution B based on the prescribed amount, and then add water for injection to the unit dose volume to obtain solution C;

[0069] S4. Filter solution C twice using a 0.22 μm filter membrane, transfer the solution into an ampoule, and then seal the ampoule directly without nitrogen filling.

[0070] Example 5

[0071] Levosalbutamol hydrochloride atomized inhalation solution composition

[0072] Prescription: 0.360 mg / mL salbutamol hydrochloride, 0.100 mg / mL co-stabilizer, 9.00 mg / mL sodium chloride, and diluted with hydrochloric acid to a pH of 4.11, with the remainder being water for injection.

[0073] The co-stabilizers are edetate disodium, gentisic acid and sodium diacetate in a mass ratio of 1:0.77:0.44.

[0074] Preparation method:

[0075] S1. Based on the prescribed amount, the osmotic pressure regulator and the co-stabilizer are added to 65% of the solvent per unit dose volume to obtain Solution A; wherein the single dose volume in this embodiment is 3 mL; the prescribed amount is based on the single dose volume, and the corresponding amounts of salbutamol hydrochloride, co-stabilizer, and osmotic pressure regulator are calculated based on the corresponding concentrations;

[0076] S2. The pH of solution A was adjusted to 4.11 using hydrochloric acid to obtain solution B;

[0077] S3. Add salbutamol hydrochloride to solution B based on the prescribed amount, and then add water for injection to the unit dose volume to obtain solution C;

[0078] S4. Filter solution C twice using a 0.22 μm filter membrane, transfer the solution into an ampoule, and then seal the ampoule directly without nitrogen filling.

[0079] Comparative Example 1

[0080] The difference between this comparative example and Example 5 is that the weight ratio of edetate disodium, gentisic acid and sodium diacetate is 1:0.4:0.2, and the rest is consistent with Example 5.

[0081] Comparative Example 2

[0082] The difference between this comparative example and Example 5 is that, in the co-stabilizer, the weight ratio of edetate disodium, gentisic acid and sodium diacetate is 1:1.5:1, and the rest is consistent with Example 5.

[0083] Comparative Example 3

[0084] The difference between this comparative example and Example 5 is that the co-stabilizer is edetate disodium, and the rest is consistent with Example 5.

[0085] Comparative Example 4

[0086] The difference between this comparative example and Example 5 is that gentisic acid is used as the co-stabilizer, and the rest is consistent with Example 5.

[0087] Comparative Example 5

[0088] The difference between this comparative example and Example 5 is that sodium diacetate is used as the co-stabilizer, and the rest is consistent with Example 5.

[0089] Comparative Example 6

[0090] The difference between this comparative example and Example 5 is that no co-stabilizer is used, nitrogen is filled and sealed in S4 of the preparation method, and the rest is consistent with Example 5.

[0091] Experimental example

[0092] Stability experimental investigation

[0093] According to the Chinese Pharmacopoeia, the purpose of the stability experiments of Examples 1-5 and Comparative Examples 1-6 was to investigate the effects of different formulation amounts on the stability of the formulations by comparing the test results of properties, pH, content, related substances, etc. The results are shown in Tables 1-3 below.

[0094] Table 1

[0095]

[0096]

[0097] The results showed that after storage at 40° C. for 6 months, no 5-hydroxysalbutamol and impurity D were detected in the salbutamol hydrochloride nebulized inhalation solution compositions of Examples 1-5, and the total impurity content was less than or equal to 0.08%. It can be seen that the salbutamol hydrochloride nebulized inhalation solution compositions provided by the present invention have excellent stability.

[0098] Table 2

[0099]

[0100]

[0101] The results showed that when the salbutamol hydrochloride nebulized inhalation solution did not use the costabilizer of the present invention or the concentration and dosage of the costabilizer exceeded the range of the present invention, 5-hydroxysalbutamol and impurity D showed an increasing trend during the accelerated 0-6 month stability process, and the total impurities increased.

[0102] Table 3

[0103]

[0104]

[0105] As can be seen from the table above, when no stabilizer is used in the nebulized inhalation solution for salbutamol hydrochloride, or all ingredients are added simultaneously during the preparation process, the 5-hydroxysalbutamol and impurity D show an increasing trend during the accelerated 0-6 month stability process, and the total impurities increase.

[0106] The above description of the embodiments is intended to facilitate understanding and application of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A salbutamol hydrochloride atomized inhalation solution composition, characterized in that: Contains 0.033mg / mL-0.500mg / mL salbutamol hydrochloride, 0.050mg / mL-0.500mg / mL co-stabilizer and 5.00mg / mL-15.00mg / mL osmotic pressure regulator, and is adjusted to a pH value of 3.30-4.50 by a pH regulator, and the rest is solvent; wherein, The co-stabilizers are edetate disodium, gentisic acid and sodium diacetate, and the weight ratio of edetate disodium, gentisic acid and sodium diacetate is 1:0.5-1.2:0.3-0.

7.

2. The salbutamol hydrochloride atomized inhalation solution composition according to claim 1, characterized in that The invention comprises 0.103 mg / mL-0.417 mg / mL salbutamol hydrochloride, 0.067 mg / mL-0.133 mg / mL co-stabilizer and 8.00 mg / mL-10.000 mg / mL osmotic pressure regulator, and is adjusted to a pH value of 3.70-4.30 by a pH regulator, with the remainder being solvent.

3. The salbutamol hydrochloride atomized inhalation solution composition according to claim 1, characterized in that In the co-stabilizer, the weight ratio of edetate disodium, gentisic acid and sodium diacetate is 1:0.7-0.9:0.4-0.

6.

4. The salbutamol hydrochloride aerosol inhalation solution composition according to any one of claims 1 to 3, characterized in that: The osmotic pressure regulator is an inorganic salt; The inorganic salt is at least one of sodium chloride, magnesium chloride or calcium chloride.

5. The salbutamol hydrochloride aerosol inhalation solution composition according to any one of claims 1 to 3, characterized in that: The pH adjuster is an acid; The acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.

6. The salbutamol hydrochloride aerosol inhalation solution composition according to any one of claims 1 to 3, characterized in that: The solvent is water for injection.

7. A method for preparing the levosalbutamol hydrochloride atomized inhalation solution composition according to any one of claims 1 to 6, characterized in that: The steps include: S1. adding an osmotic pressure regulator and a co-stabilizer to a solvent and dissolving them to obtain a solution A; S2. adjusting the pH of solution A to a target value with a pH adjuster to obtain solution B; S3. Levosalbutamol hydrochloride is added to solution B, and then solvent is added to the volume to obtain solution C; S4. Filter solution C to obtain the product.

8. The method according to claim 7, characterized in that In step S1, the temperature of the solvent is ≤30°C.

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